Use of heterocyclic compounds in the treatment of pigmented skin

Abstract

Disclosed herein are compounds for use in lightening skin, treating uneven skin pigmentation and/or improving the appearance of aging skin, as well as methods utilizing the compounds, and anti-aging compositions comprising the compounds and a pharmaceutically acceptable carrier. The compounds have the general Formula I:or a pharmaceutically acceptable salt thereof, wherein the dashed line, X, Y, Z, Ra-Rd, and R1-R3 are as defined herein.

What is claimed is: 
     
       1. A method of lightening skin in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the general Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         the dashed line denotes a saturated or non-saturated bond; 
         X is selected from the group consisting of CH, C and N, such that when X is C the dashed line denotes a non-saturated bond and when X is CH or N the dashed line denotes a saturated bond; 
         Y is N or CR 4 ; 
         Z is N or CR 5 ; and 
         Ra-Rd, and R 1 -R 5  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide, sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl, phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, each being substituted or non-substituted, 
         thereby lightening the skin. 
       
     
     
       2. The method of  claim 1 , wherein at least one of R 1 -R 5  is selected from the group consisting of hydroxy and a moiety having the general Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         A is selected from the group consisting of C and S═O; 
         B is absent or is a substituted or non-substituted, saturated or non-saturated alkylene chain; and 
         D is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide, sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl, phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, each being substituted or non-substituted. 
       
     
     
       3. The method of  claim 2 , wherein R 1  is selected from the group consisting of hydroxy and said moiety having the general Formula II. 
     
     
       4. The method of  claim 2 , wherein said A is a carbon atom. 
     
     
       5. The method of  claim 1 , wherein R 2 -R 5  are each hydrogen. 
     
     
       6. The method of  claim 1 , wherein Ra-Rd are each hydrogen. 
     
     
       7. The method of  claim 1 , wherein said X is N. 
     
     
       8. The method of  claim 1 , wherein said Y is CR 4  and said Z is CR 5 . 
     
     
       9. The method of  claim 1 , wherein said compound is 2-((4-(3-hydroxyphenyl)piperazin-1-yl)methyl)quinazolin-4-one: 
       
         
           
           
               
               
           
         
       
     
     
       10. A method of treating uneven skin pigmentation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the general Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         the dashed line denotes a saturated or non-saturated bond; 
         X is selected from the group consisting of CH, C and N, such that when X is C the dashed line denotes a non-saturated bond and when X is CH or N the dashed line denotes a saturated bond; 
         Y is N or CR 4 ; 
         Z is N or CR 5 ; and 
         Ra-Rd, and R 1 -R 5  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide, sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl, phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, each being substituted or non-substituted, 
         thereby treating the uneven skin pigmentation. 
       
     
     
       11. The method of  claim 10 , wherein at least one of R 1 -R 5  is selected from the group consisting of hydroxy and a moiety having the general Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         A is selected from the group consisting of C and S═O; 
         B is absent or is a substituted or non-substituted, saturated or non-saturated alkylene chain; and 
         D is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide, sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl, phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, each being substituted or non-substituted. 
       
     
     
       12. The method of  claim 11 , wherein R 1  is selected from the group consisting of hydroxy and said moiety having the general Formula II. 
     
     
       13. The method of  claim 11 , wherein said A is a carbon atom. 
     
     
       14. The method of  claim 10 , wherein R 2 -R 5  are each hydrogen. 
     
     
       15. The method of  claim 10 , wherein Ra-Rd are each hydrogen. 
     
     
       16. The method of  claim 10 , wherein said X is N. 
     
     
       17. The method of  claim 10 , wherein said Y is CR 4  and said Z is CR 5 . 
     
     
       18. The method of  claim 10 , wherein said compound is 2-((4-(3-hydroxyphenyl)piperazin-1-yl)methyl)quinazolin-4-one: 
       
         
           
           
               
               
           
         
       
     
     
       19. A method of improving the appearance of aging skin in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the general Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         the dashed line denotes a saturated or non-saturated bond; 
         X is selected from the group consisting of CH, C and N, such that when X is C the dashed line denotes a non-saturated bond and when X is CH or N the dashed line denotes a saturated bond; 
         Y is N or CR 4 ; 
         Z is N or CR 5 ; and 
         Ra-Rd, and R 1 -R 5  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide, sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl, phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, each being substituted or non-substituted, 
         thereby improving the appearance of the aging skin. 
       
     
     
       20. The method of  claim 19 , wherein at least one of R 1 -R 5  is selected from the group consisting of hydroxy and a moiety having the general Formula II: 
       
         
           
           
               
               
           
         
         wherein: 
         A is selected from the group consisting of C and S═O; 
         B is absent or is a substituted or non-substituted, saturated or non-saturated alkylene chain; and 
         D is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heteroalicyclic, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, thiohydroxy, thioalkoxy, thioaryloxy, halide, amine, amide, carbonyl, thiocarbonyl, carboxy, thiocarboxy, epoxide, sulfonate, sulfonyl, sulfinyl, sulfonamide, nitro, nitrile, isonitrile, thiirane, aziridine, nitroso, hydrazine, sulfate, azide, phosphonyl, phosphinyl, urea, thiourea, carbamyl and thiocarbamyl, each being substituted or non-substituted. 
       
     
     
       21. The method of  claim 20 , wherein R 1  is selected from the group consisting of hydroxy and said moiety having the general Formula II. 
     
     
       22. The method of  claim 20 , wherein said A is a carbon atom. 
     
     
       23. The method of  claim 19 , wherein R 2 -R 5  are each hydrogen. 
     
     
       24. The method of  claim 19 , wherein said X is N. 
     
     
       25. The method of  claim 19 , wherein said Y is CR 4  and said Z is CR 5 . 
     
     
       26. The method of  claim 19 , wherein said compound is 2-((4-(3-hydroxyphenyl)piperazin-1-yl)methyl)quinazolin-4-one: 
       
         
           
           
               
               
           
         
       
     
     
       27. The method of  claim 1 , wherein said administering comprises topical administration. 
     
     
       28. The method of  claim 27 , wherein said compound forms a part of a pharmaceutical composition formulated for topical administration. 
     
     
       29. The method of  claim 10 , wherein said administering comprises topical administration. 
     
     
       30. The method of  claim 19 , wherein said administering comprises topical administration.